Search results for "Epigenetic"
showing 10 items of 632 documents
The emergence of drug resistance to targeted cancer therapies: Clinical evidence.
2019
For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance deve…
Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair
2015
Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. In addition, classical regulation of gene expression or activity, including gene transcription to RNA followed by translation to the protein level, by transcription factors (e.g. NF-κB, HIF-1α) and mRNA binding proteins (e.g. GAPDH, HuR) is subject to redox regulation. This review will give an update of recent discoveries in this field, and specifically highlight the impact of reactive oxygen and nitrogen species on DNA repair systems that contribute to genomic stability. Emphasis will be placed …
Alignment Free Dissimilarities for Nucleosome Classification
2016
Epigenetic mechanisms such as nucleosome positioning, histone modifications and DNA methylation play an important role in the regulation of cell type-specific gene activities, yet how epigenetic patterns are established and maintained remains poorly understood. Recent studies have shown a role of DNA sequences in recruitment of epigenetic regulators. For this reason, the use of more suitable similarities or dissimilarity between DNA sequences could help in the context of epigenetic studies. In particular, alignment-free dissimilarities have already been successfully applied to identify distinct sequence features that are associated with epigenetic patterns and to predict epigenomic profiles…
CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2.
2018
Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP…
I vari modi del DNA di “parlare” ai viventi fra ciò che già è noto e nuove scoperte
2018
A sessant’anni da quando Francis Crick enunciò il “dogma centrale della biologia molecolare” molte scoperte e nuove frontiere si sono avvicendate sulla questione “funzionale” di un genoma, cioè di come un DNA “parla” ai viventi. Oggi è abbastanza noto come un genoma “è”, ed occuparsi solo di questa questione strutturale ormai è sicuramente molto riduttivo, almeno sicuramente per quello umano. È invece il goal standard di questi anni scoprire come e quando un genoma si esprime, come funzio-nalmente traduce il suo messaggio rendendo questo visibile nei fe-notipi dei viventi, a prescindere dalla sua sequenza primaria di basi azotate. Ne consegue che il codice genetico, ancora valido e quasi un…
Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells
2009
Epigenetic mechanisms that maintain neurogenesis throughout adult life remain poorly understood(1). Trithorax group (trxG) and Polycomb group (PcG) gene products are part of an evolutionarily conserved chromatin remodelling system that activate or silence gene expression, respectively(2). Although PcG member Bmi1 has been shown to be required for postnatal neural stem cell self-renewal(3,4), the role of trxG genes remains unknown. Here we show that the trxG member Mll1 (mixed-lineage leukaemia 1) is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate and efficiently differentiate into glial lineages; however, neur…
Usher syndrome: molecular links of pathogenesis, proteins and pathways.
2006
Contains fulltext : 50437.pdf (Publisher’s version ) (Closed access) Usher syndrome is the most common form of deaf-blindness. The syndrome is both clinically and genetically heterogeneous, and to date, eight causative genes have been identified. The proteins encoded by these genes are part of a dynamic protein complex that is present in hair cells of the inner ear and in photoreceptor cells of the retina. The localization of the Usher proteins and the phenotype in animal models indicate that the Usher protein complex is essential in the morphogenesis of the stereocilia bundle in hair cells and in the calycal processes of photoreceptor cells. In addition, the Usher proteins are important in…
Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging
2021
Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci ass…
Oxidative stress and antioxidants in the pathophysiology of malignant melanoma.
2018
Abstract The high number of somatic mutations in the melanoma genome associated with cumulative ultra violet (UV) exposure has rendered it one of the most difficult of cancers to treat. With new treatment approaches based on targeted and immune therapies, drug resistance has appeared as a consistent problem. Redox biology, including reactive oxygen and nitrogen species (ROS and RNS), plays a central role in all aspects of melanoma pathophysiology, from initiation to progression and to metastatic cells. The involvement of melanin production and UV radiation in ROS/RNS generation has rendered the melanocytic lineage a unique system for studying redox biology. Overall, an elevated oxidative st…
Colorectal Cancer Stem Cells: From the Crypt to the Clinic
2014
Since their first discovery, investigations of colorectal cancer stem cells (CSCs) have revealed some unexpected properties, including a high degree of heterogeneity and plasticity. By exploiting a combination of genetic, epigenetic, and microenvironmental factors, colorectal CSCs metastasize, resist chemotherapy, and continually adapt to a changing microenvironment, representing a formidable challenge to cancer eradication. Here, we review the current understanding of colorectal CSCs, including their origin, relationship to stem cells of the intestine, phenotypic characterization, and underlying regulatory mechanisms. We also discuss limitations to current preclinical models of colorectal …